Technical Abstract:
The rates of cell proliferation and cell loss in conjunction with the differentiation status of the tissue are among the many factors contributing to carcinogenesis. Non-genotoxic (non-DNA reactive) chemicals may affect this balance by increasing proliferation through direct mitogenesis or through a regenerative response following loss of cells through cytotoxic (oncotic) or apoptotic necrosis. In a recent NTP study in Fischer rats and B6C3F1 mice, the mycotoxin fumonisin (FB1) caused renal carcinomas in male rats and liver cancer in female mice. In an earlier study in male BDIX rats, FB1 caused hepatic toxicity and hepatocellular carcinomas. It as also been shown to cause liver cancer in female mice. An early effect of FB1 exposure in these target organs is apoptosis. However, there is also some evidence of oncotic necrosis following FB1 administration, especially in the liver. Induction of apoptosis may be a consequence of ceramide synthase inhibition and disruption of sphingolipid metabolism by FB1. FB1 is not genotoxic in bacterial mutagenesis screens or in the rat liver unscheduled DNA synthesis assay. FB1 may be the first example of an apparently non-genotoxic (non-DNA reactive) agent producing tumors through a mode of action involving apoptotic necrosis, atrophy, and consequent regeneration.